Our long-standing interest is in synaptic plasticity, but we are exploring new mechanisms of nervous system plasticity that extend beyond the neuron doctrine. We are especially interested in the involvement of glial cells in learning & cognition. Glia are brain cells that do not fire electrical impulses, but they communicate by releasing neurotransmitters. This enables glia to monitor & regulate nervous system function. Myelinating glia (oligodendrocytes in the brain & Schwann cells in the body) form the electrical insulation on axons that greatly speeds impulse conduction velocity. Damage to myelin in multiple sclerosis, cerebral palsy, & other demyelinating disorders, causes severe nervous system impairment. Our research shows that myelination of axons is regulated by impulse activity. This suggests a new form of nervous system plasticity & cellular mechanism of learning that would be particularly important in child development, because myelination proceeds through childhood & adolescence. Early life experience, both adverse & enriching, influences development of the brain in ways that can persist into adulthood. Rather than directly modifying synaptic transmission, activity-dependent myelination alters the speed & timing of information transmitted between relay points in neural networks. The arrival time of neural impulses at relay points in neural networks is of fundamental importance in neural coding, neuronal integration & synaptic plasticity, & in the coupling of brainwave oscillations. We have identified several molecular mechanisms for activity-dependent myelination & shown that electrically active axons are preferentially myelinated. The laboratory has three areas of current research interest 1. Investigating how neurons & glia interact, communicate, & cooperate functionally. A major emphasis is in understanding how myelin is involved in learning, cognition, child development, & psychiatric disorders. We are determining how glia sense neural impulse activity & investigating the functional & developmental consequences. 2. We are also investigating how myelination in the peripheral nervous system (PNS) may be influenced by neural impulse activity. Myelin in the PNS is formed differently than in the brain. Far less is known about PNS myelination, but normal child development & recovery from nerve injury & disease require appropriate myelination. 3. Functional experience influences nervous system development & plasticity by guiding appropriate changes in specific proteins & genes that regulate neural network formation & function. We are determining how different patterns of neural impulses regulate specific genes controlling development & plasticity of the nervous system. Our research goals advance 4 of the 6 NICHD research themes: 1. Understanding Early Human Development, 2. Setting the Foundation for a Healthy Pregnancy & Lifelong Wellness, 3. Identifying Sensitive Time Periods to Optimize Health Interventions, & 4. Improving Health During the Transition from Adolescence to Adulthood. Myelin Plasticity Myelination is an essential part of brain development that begins in the second trimester & continues through adolescence, but myelination of some brain regions is not completed until the early twenties. The last part of the brain to complete myelination is the prefrontal cortex, the brain region responsible for impulse control & other executive functions. Environmental and other influences on myelination of the prefrontal cortex during adolescences contribute to neuropsychiatric concerns, including social interactions, decision making, anxiety disorders, & impulsivity. Many pediatric disorders, including cerebral palsy, dyslexia, language development, spasticity, & developmental delay are associated with disorders of myelin, in addition to well recognized demyelinating disorders, such as multiple sclerosis. Our research shows that the neurotransmitter glutamate released from vesicles along axons initiates myelin formation. This signaling promotes myelination of electrically active axons to regulate neural development & function according to environmental experience. We also find that other signaling molecules released from axons, notably ATP, regulate development of myelinating glia. This nonsynaptic communication could mediate various activity-dependent interactions between axons & nervous system cells in normal conditions, development, & disease. Myelin Remodeling Our most recent research extends beyond the question of how impulse activity influences formation of myelin, & reveals that the structure of fully-formed myelin can change to adjust conduction velocity to optimize neural circuit function. Previously, it was assumed that myelin could not be altered, except by damage, but our research finds that myelin thickness & the node of Ranvier can be remodeled by a treadmilling process in which the outer layer of myelin wrapping is removed to thin the myelin sheath & slow conduction velocity, & new myelin is added beneath the overlaying layers to thicken the sheath. We find that glial cells called astrocytes, regulate the detachment of this outer layer of myelin from the axon by secreting molecules (thrombin protease inhibitors), that inhibit severing of the molecules that attach myelin to the axon (neurofascin 155). White Matter Damage Myelin damage is associated with many medical conditions, including hypoxia/ischemia during birth leading to cerebral palsy, exposure to environmental toxins such as pesticides, autoimmune disorders such as multiple sclerosis, & other conditions. We are investigating the possible involvement of myelin disruption in these contexts & seeking to develop new biomarkers & treatments for these conditions. Gulf War Illness, for example, continues to afflict veterans of the Gulf War, 25 years after that conflict ended, & the cause remains obscure. Our research shows that exposure to low-level nerve toxins (acetylcholine esterase inhibitors) impairs normal development & function of oligodendrocytes; thus implicating disruption of myelin in the pathological mechanism of this disorder. This also answers how an acute exposure to an adverse agent 25 years ago, could cause persistent disability, & it provides a compelling example of how environmental influences during sensitive periods can lead to persistent adverse health consequences. PNS Myelination Myelin is formed in the PNS by Schwann cells, which are entirely different types of cells from oligodendrocytes which form myelin in the CNS. Far less is known about Schwann cell myelination, but normal development & many disorders are the result of disruption of PNS myelin, including diabetic neuropathy, Gillian Barre disease, & recovery from all nerve injury which results in damage to myelin. We are applying our findings on activity-dependent myelination by oligodendrocytes to determine if similar mechanisms regulate PNS myelination. Activity-Dependent Gene Regulation Using optogenetic stimulation in vivo & electrical stimulation in co-cultures, together with microarray and RNA sequencing, we are determining how gene networks & chromatin structure in neurons & glia are regulated by the pattern of neural impulse firing. Our studies show that specific patterns of action potentials regulate expression of thousands of genes in neurons and glia.